As used herein, obesity is meant to comprise any increase in body fat that results in increased bodyweight and includes the medical definition of obesity. Thus, obesity also comprises any body fat increase not meeting the medical definition of obese, e.g. cosmetically overweight. The present disclosure relates to non-medical weight loss, such as cosmetic weight loss and includes improving body appearance in general. In one sense, obesity is understood to denominate a body weight more than 20% above the ideal body weight. In this sense, obesity is a major health concern in Western societies. It is estimated that about 97 million adults in the United States are overweight or obese. Obesity is largely the result of a positive energy balance as a consequence of increased ratio of caloric intake to energy expenditure. The molecular factors regulating food intake and body weight are not completely understood, but several genetic factors have been identified.
Epidemiological studies have shown that increasing degrees of overweight and obesity are important predictors of decreased life expectancy. Obesity causes or exacerbates many health problems, both independently and in association with other diseases. The problems associated with obesity, which can be serious and life-threatening, are well-known and generally include hypertension; type II diabetes mellitus; elevated plasma insulin concentrations; insulin resistance; dyslipidemias; hyperlipidemia; endometrial, breast, prostate and colon cancer; osteoarthritis; respiratory complications, such as obstructive sleep apnea; cholelithiasis; gallstones; arteriosclerosis; heart disease; abnormal heart rhythms; and heart arrythmias. Obesity is further associated with premature death and with a significant increase in mortality and morbidity from stroke, myocardial infarction, congestive heart failure, coronary heart disease, and sudden death.
Obesity is often treated by encouraging patients to lose weight by reducing their food intake or by increasing their exercise level and therefore increasing their energy output. A sustained weight loss of 5% to 10% of body weight has been shown to improve the co-morbidities associated with obesity, such as diabetes and hypertension, and can lead to improvement of obesity-related conditions such as osteoarthritis, sleep apnea and pulmonary and cardiac dysfunction.
Weight loss drugs that are currently used in monotherapy for the treatment of obesity have limited efficacy and significant side effects. During chronic treatment periods of greater than six months, the efficacy of most agents decreases yielding no more than 10% body weight loss compared to control. Obese humans can easily have a body mass of over 150 kg and would, therefore, need to lose more than 50% of their body mass to return to a normal body mass.
The term “metabolic syndrome” is meant to cover a complex of clinical manifestations which, besides central obesity, mainly comprises hypertension, in particular arterial hypertension; insulin resistance, in particular type II diabetes; glucose intolerance; dyslipoproteinaemia, in particular as hypertriglyceridaemia, accompanied by dyslipoproteinaemia occurring with lowered HDL-cholesterol, and also hyperuricaemia, which can lead to gout.
According to information from the American Heart Association, metabolic syndrome is closely linked to insulin resistance. Some people are genetically predisposed to insulin resistance. Acquired factors, such as excess body fat and physical inactivity, can elicit insulin resistance and metabolic syndrome in these people. Many people with insulin resistance have central obesity. The biological mechanisms at the molecular level between insulin resistance and metabolic risk factors are not fully understood and appear to be complex. One group of people at risk for developing metabolic syndrome is those with diabetes who have a defect in insulin action and cannot maintain a proper level of glucose in their blood. Another is people, mainly those with high blood pressure, who are non-diabetic and insulin-resistant but who compensate by secreting large amounts of insulin. This condition is known as hyperinsulinemia. A third group is heart attack survivors who, unlike hypertensives, have hyperinsulinemia without having abnormal glucose levels. Metabolic syndrome has become increasingly common in more developed countries like the United States, where it is estimated that between about 20% and 25% of US adults have metabolic syndrome. There are no well-accepted criteria for diagnosing the metabolic syndrome. The criteria proposed by the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) are the most current and widely used. According to the Adult Treatment Panel III criteria, the metabolic syndrome is identified by the presence of three or more of these following components:                a. Central obesity as measured by waist circumference (Men—Greater than 40 inches; Women—Greater than 35 inches).        b. Fasting blood triglycerides greater than or equal to 150 mg/dL.        c. Blood HDL cholesterol (Men—Less than 40 mg/dL; Women—Less than 50 mg/dL).        d. Blood pressure greater than or equal to 130/85 mmHg.        e. Fasting glucose greater than or equal to 110 mg/dL.        
The term “syndrome X” is closely related to the term “metabolic syndrome” and is typically used to indicate the identical disease or condition. According to information from the American Heart Association, the term “Syndrome X” refers, however, additionally to a heart condition where chest pain and electrocardiographic changes that suggest ischemic heart disease is present, but where there are no angiographic findings of coronary disease. Patients with cardiac syndrome X also sometimes have lipid abnormalities.
Therefore, one embodiment disclosed herein provides a more effective and/or more selective therapy for obesity, diabetes mellitus, metabolic syndrome and/or syndrome X.
ATP-sensitive potassium channel (KATP channel) modulation has been linked to several potential clinical uses including diabetes, insulinoma, familial hyperinsulemic hypoglycemia, male pattern baldness, detrusor hyperreactivity, asthma, neuroprotection, epilepsy, analgesia, cardioprotection, angina, cardioplegia, arrhythmia, coronary spasm, hypertension, peripheral vascular disease, cerebral vasospasm, appetite regulation, neurodegeneration, pain, neuropathic pain, chronic pain, idiopathic pain and impotence (ref. Jahangir et al. J. Mol. Cell. Cardiology, 2005, 39, 99-112 and references cited therein).
Blockers of Kir6.2/SUR1 KATP channels (e.g. repaglinde, tolbutamide and glibenclamide) stimulate insulin release and are used in the treatment of type II diabetes.
KATP channel openers and their potential use in the inhibition of insulin secretion and/or the treatment of metabolic disorders are discussed in U.S. Pat. No. 6,492,130; WO 02/00223; WO 02/00665 or from R. D. Carr et al., Diabetes 52 (2003) 2513-2518 or J. B. Hansen et al., Current Medicinal Chemistry 11 (2004) 1595-1615.
The beneficial role of the specific KATP channel opener diazoxide in the treatment of i.a. metabolic syndrome is discussed in U.S. Pat. No. 5,284,845 or U.S. Pat. No. 6,197,765 or from R. Alemzadeh et al., Endocrinology 133 (2) (1993) 705-712 or R. Alemzadeh et al., Journal of Clinical Endocrinology and Metabolism 83 (6) (1998) 1911-1915.
The KATP channel couples glucose metabolism to insulin secretion. Defective regulation of KATP channel activity has been reported to contribute to the etiology of type 2 diabetes (ref. Ashcroft, J. Clin. Investig. 2005, 115 (8), 2047-2057 and references cited therein). The KATP, channel is an octameric complex of 4 Kir6.x (x=1 or 2) and 4 regulatory SURy subunits (Y=1, 2A or 2B). The SUR1 regulatory subunit is in particular found in the human pancreas and brain (ref. Aguilar-Bryan et al., Science 1995, 268, 423-426). The KATP Kir6.2/SUR1 combination exists in the pancreas. Its structure has been determined recently (ref. Mikhailov, EMBO Journal, 2005, 24, (23), 4166-4175). Advances in the discovery of ATP-sensitive potassium channel openers have been recently reviewed in Pirotte et al., Exp Opin. Ther. Patents 2005, 15 (5), 497-504 and Hansen, Curr. Med. Chem. 2006, 13, 361-76.
Insulin is the main hormone involved in blood glucose homeostasis. Insulin is involved in the regulation of glycaemia and as a consequence related to type I and type II diabetes. Additionally, insulin is involved in lipogenesis and weight gain, provoking an anorexigenic action as it provokes satiety when acting in the brain (ref. Juan-Pico et al., Cell Calcium 2006, 39, 155-163 and references cited therein).
Therefore, the regulation of insulin secretion will be useful in the treatment of diseases such as diabetus mellitus type I, diabetus mellitus type II, obesity, metabolic syndrome and syndrome X.
The endocannabinoid system (refs. (a) De Petrocellis, L. et al., Br, J. Pharmacol. 2004 141, 765-774; (b) Di Marzo, V. et al., Nature Rev. Drug Discov. 2004, 3, 771-784; (c) Lambert, D. M. and Fowler, C. J. J. Med. Chem. 2005, 48, 5059-5087) has been reported to play a role in the physiological regulation of food intake, energy balance and glucose and lipid metabolism. The existence of both cannabinoid CB1 and CB2 receptors has been demonstrated in the endocrine pancreas. It has been reported that the endogenous CB1/2 receptor agonist 2-arachidonoyl glycerol (2-AG) (FIG. 2) through CB2 receptors regulates [Ca2+]i signals in β-cells in the endocrine pancreas and, as a consequence (as was concluded by Juan-Pico et al.), it decreases insulin secretion (ref. Juan-Pico et al., Cell Calcium 2006, 39, 155-163). Recent advances in the field of CB2 receptor ligands have been reviewed by Raitio et al. (Curr. Med. Chem. 2005, 12, 1217-1237).
It has now surprisingly been found that a novel combination therapy which comprises administering a first KATP channel modulator and a first CBx modulator to a patient in need thereof can provide an effective and/or selective therapy for a variety of medical conditions such as obesity, diabetes mellitus, metabolic syndrome, syndrome X, insulinoma, familial hyperinsulemic hypoglycemia, male pattern baldness, detrusor hyperreactivity, asthma, neuroprotection, epilepsy, analgesia, cardioprotection, angina, cardioplegia, arrhythmia, coronary spasm, peripheral vascular disease, cerebral vasospasm, appetite regulation, neurodegeneration, pain, neuropathic pain, chronic pain, idiopathic pain and impotence in mammals such as humans. More specifically, due to the long term effect of therapy with a KATP channel modulator, this new combination therapy is particularly suited for the treatment of diabetes mellitus, metabolic syndrome and/or syndrome X in patients exposed to an elevated risk of acquiring such diseases, such as patients with established obesity. However, due to its direct effect on glucose metabolism, the novel combination therapy according to the present disclosure is also well suited to treat type II diabetes and insulin resistance in patients without concomitant obesity.